Abstract

The matrix metalloproteinases (MMPs) are perceived as essential for tumour invasion and metastases. The purpose of this study was to determine the expression and cellular localisation of the 92 kDa type IV collagenase (MMP-9) protein and mRNA in human colorectal cancer (CRC). In CRC and matched normal mucosa specimens from 26 CRC patients, Northern blot hybridisation and Western blot analyses provide convincing evidence that MMP-9 is expressed in greater quantities in CRC than in normal tissue. The MMP-9 tumour to normal mucosa fold-increase (T/N) was 9.7 +/- 7.1 (mean +/- s.d.) (P < 0.001) for RNA and 7.1 +/- 3.9 (P < 0.001) for protein. The sites of MMP-9 mRNA and protein synthesis were colocalised in tumour stroma by in situ hybridisation and immunohistochemistry in 26 CRC samples. Both MMP-9 mRNA and protein signals were strongest in the population of stromal cells concentrated at the tumour-stroma interface of an invading tumour. Furthermore, MMP-9-positive cells were identified as macrophages using an antimacrophage antibody (KP1) in serial sections from ten CRC samples. Given the persistent localisation of MMP-9-producing macrophages to the interphase between CRC and surrounding stroma, our observations suggest that MMP-9 production is controlled, in part, by tumour-stroma cell interactions. Further studies are needed to determine the in vivo regulation of MMP-9 production from infiltrating peritumour macrophages.

Highlights

  • Crucial steps in tumour invasion and metastases are the breaching of the basement membrane (BM) and degradation of the extracellular matrix (ECM) (Liotta et al, 1991; Matrisian, 1992)

  • Total cellular RNA of human colorectal cancer (CRC) and paired adjacent normal mucosa from 26 CRC patients was examined for expression of matrix metalloproteinases (MMPs)-9 RNA by Northern blot hybridisation

  • The 2.8 kb MMP-9 transcript was strongly expressed in tumour compared with the extremely low levels noted in normal mucosa

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Summary

Introduction

Crucial steps in tumour invasion and metastases are the breaching of the basement membrane (BM) and degradation of the extracellular matrix (ECM) (Liotta et al, 1991; Matrisian, 1992). These processes are likely to involve numerous proteolytic enzymes, including matrix metalloproteinases (MMPs), a family of extracellular matrix-degrading enzymes (Liotta et al, 1991). At least 14 members of the MMP family have been described by substrate specificity (Birkedal-Hansen, 1995). MMPs can be subclassified into interstitial collagenases

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